Ketamine induces growth of tiny protuberances on a rat neuron (bottom) to allow it to better connect with neighbors.

Recent experimental research showing that the anesthetic and club drug ketamine can relieve depression quickly has intrigued a number of major pharmaceutical companies. Depression, it goes without saying, affects huge numbers and a fundamentally new and effective pharmaceutical approach to treating the disorder hasn’t emerged in decades.

The enthusiasm for ketamine is such that physicians, often working out of small clinics, have already started prescribing low doses of the generic anesthetic off-label for fast relief of le cafard—and drug companies are contemplating whether to get into the act by creating new drugs based on ketamine's biochemistry (Read part 1 and part 2).

A Johnson & Johnson subsidiary in Europe has gone as far as midstage clinical trials for a ketamine nasal spray. The trial there uses a slightly altered version of ketamine (esketamine, the “s” isomer for techies), which omits part of the molecule and leaves the most pharmacologically active portion in place, enabling less of the compound to be administered. "You can get away with a 30 to 40 percent lower dose," says Husseini Manji who leads neuroscience research at Johnson & Johnson.

The U.S. Food and Drug Administration has put Johnson & Johnson’s version of esketamine on a fast track for approval, although, even if all goes well, patients may still have to wait a years to get a script. Esketamine, already used as an anesthetic in Europe, is not the only idea on the table. Ketamine appears to work (details still coming in from labs) by blocking a docking site, or receptor, on a neuron—in this case a spot where the essential signaling molecule glutamate attaches. The blockade triggers a complex chemical cascade that ends up restoring an impaired neuron’s ability to communicate with other brain cells.

If that process is multiplied over millions of neurons in two critical brain regions—the hippocampus and the prefrontal cortex—drugmakers hope the blues will lift like a cloud. Johnson & Johnson is working on other projects that tap into ketamine research—one of which is looking at a wholly new drug that targets selected portions of this glutamate receptor in the hope of fine-tuning the antidepressant effects further. Other large pharmas, including AstraZeneca and Roche, are pursuing similar strategies.

If a formal FDA imprimatur is forthcoming, the issue of off-label prescribing may persist. One issue, which must be resolved through clinical trials rather than trial and error at ketamine clinics, is whether a spray works as well as intravenous infusions. The generic non-isomer form of ketamine is already used off-label as a nasal spray and not all reviews are positive. “It helped but not as much as the infusion,” says Dennis Hartman, a patient with depression who sought help from ketamine-prescribing physicians, one of whom provided a spray.

A ketamine-like drug, if approved, will inevitably be more expensive than the generic anesthetic deployed in upstart depression clinics. Esketamine or one of its FDA-sanctioned cousins will probably be covered via a health insurance plan, but insurers’ love of low-cost generics may mean that consideration could still be given to covering plain-vanilla ketamine, even if it hasn’t run the clinical-trial gantlet. In fact, Carlos Zarate, a leading ketamine researcher who works at the National Institute of Mental Health, has even fielded calls from insurers wanting to know more about the generic drug to determine whether to put it on their formularies.

It is also still unclear whether the medical establishment, with a helping hand from law enforcement, may have to come to terms with what might be described as off–off-label prescribing—the depressed patient without insurance who learns about the possibility of a mood-altering quick fix and engages in the unsupervised self administration of Special K purchased in a club or on the street.

Hartman knows someone who went this route. “This personal friend received a ketamine infusion [from a physician],” Hartman says. "He achieved very strong relief, very similar to mine. After he relapsed, he went and sought this illegal form and he did not get the same effect.” If Johnson & Johnson’s esketamine trials result in a salable drug, the company has plans to safeguard it from those who want to divert it for recreational use.

What to do about ketamine is a question being posed everywhere, not just stateside. A New Zealand government official issued a report in July that instructed health boards throughout the country to scrutinize off-label prescribing more closely after a complaint lodged against a ketamine-supplying physician.

Inevitably, the grassroots appeal of an old drug with a new use that might provide hope for the deeply depressed is starting to generate its own social networks. As many as 20 physicians involved in prescribing ketamine interact on the Linked-In group called Ketamine for Psychiatry. Hartman is involved with setting up a new Web site, The Ketamine Advocacy Network, to foster activism among patients—another echo of medical marijuana’s legacy.

The desperation to find new antidepressants means that ketamine will remain an object of fascination for mental health professionals and their patients. In the next five years, regulators and physicians are going to have to figure out how, if at all, the drug fits into the psychiatrist’s pharmacopoeia. In the meantime, doctors and patients are increasingly adopting their own home-grown solutions.

Image Source: Ronald Duman, Yale University

ABOUT THE AUTHOR(S)

Gary Stix

Gary Stix is a senior editor at Scientific American. He writes the blog Talking Back at ScientificAmerican.com.

Is Ketamine Right for You? Off-Label Prescriptions for Depression Pick Up in Small Clinics, Part 2

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